Opioid drugs, such as morphine, have long been used to treat patients suffering from pain. Opioid drugs exert their analgesic and other pharmacological effects through interactions with opioid receptors: mu (μ) receptors, kappa (κ) receptors, delta (δ) receptors, and sigma (σ) receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opiate mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation. Sigma receptors mediate various biological activities.
The existence of the opioid delta receptor is a recent discovery which followed the isolation and characterization of endogenous enkephalin peptides which are ligands for the delta receptor. Research has produced significant information about the delta receptor, but a clear understanding of its function has not yet emerged. Delta receptors mediate analgesia, but do not appear to inhibit intestinal transit in the manner characteristic of mu receptors.
Pharmacologically, opioid drugs represent a class of agents employed in the management of pain, and also in combating drug addiction, alcohol addiction, drug overdose, mental illness, urinary incontinence, cough, lung edema, diarrhea, depression, and cognitive, respiratory, and gastro-intestinal disorders. Unfortunately, the use of opioid drugs is associated with the potential for abuse. In addition, oral administration of opioid drugs often results in significant first pass metabolism. Furthermore, administration of opioid drugs results in significant CNS-mediated effects, such as slowed breathing, which may result in death. Thus, a reduction of any one of these or other characteristics would enhance their desirability as therapeutic agents.
Recently, a class of potent and selective delta opioid receptor binding agents, diarylpiperazines (including compound BW373U86), has been described (See U.S. Pat. No. 5,658,908, and Chang, K. J., et al.; J. Pharmacol. Exp. Ther. 267, 852-857 (1993)). However, preliminary experiments have suggested that BW373U86 may produce an increase in hyperactivity, including convulsions (Comer, S., et al; J. Pharmacol. Exp. Ther. 267, 888-895 (1993)). Therefore, pharmacotherapy with opioid diarylpiperazines would be improved if these and/or other side effects associated with their use could be decreased or if their pharmacology could be improved. Thus, there is a large unmet need for developing novel opioid diarylpiperazine compounds.
The present invention seeks to address these and other needs in the art.